1. Field of the Invention
The present invention relates to cyclodextrin derivatives and to their pharmaceutical application as clathrating agents.
2. Discussion of the Background
Cyclodextrins (CD) are a group of cyclic homologous oligosaccharides that are obtained from the degradation of starch by the action of the enzyme cyclodextrin transglycosylase elaborated by the bacterium Bacillus macerans. Published methods exist for the production of cyclodextrin transglycosylase as well as making and isolating the cyclodextrins.
Cyclodextrins are cyclic molecules containing six or more .alpha.-D-glucopyranose units linked at the 1,4 positions by .alpha. linkages as in amylose. As a consequence of this cylic arrangement, the molecule is characterized as having neither a reducing end group nor a non-reducing end group.
The molecule is represented below by schematic formula (1) where the hydroxyl groups are shown in the 2, 3, and 6-positions of the glucopyranose units. ##STR1## Variable n may be a number from 4 to 6, or higher.
When n=4 the molecule is commonly known as .alpha.-cyclodextrin or cyclohexaamylose, when n=5 the molecule is commonly known as .beta.-cyclodextrin or cycloheptaamylose and when n=6 the molecule is commonly known as .gamma.-cyclodextrin or cycloctaamylose. When reference is made here to "cyclodextrin", it is intended to include the foregoing forms of cyclodextrin as well as molecules where n&gt;6.
It is believed that as a consequence of the cylic arrangement and the conformation of the .beta.-D-glucopyranose units, there is limited free rotation about the glycosidic bonds, and the cyclodextrins exist as conical shaped molecules with the primary hydroxyls situated at the small end of the cone and the secondary hydroxyls situated at the large opening to the cone. The cavity is lined by hydrogen atoms from C.sub.3 and C.sub.5 along with the glucosidic oxygen atoms resulting in a relatively lipophilic cavity but hydrophilic outer surface.
As a result of the two separate polar regions and the changes in solvent structure that occur upon complexation, cyclodextrins have the ability to form complexes with a variety of organic and inorganic molecules. The formation of cyclodextrin inclusion complexes with molecules is referred to as the host-guest phenomenon.
These unique properties of cyclodextrins have resulted in their commercial application in agriculture, water treatment, as surfactants and in drug delivery systems. The application of cyclodextrins in the pharmaceutical field has resulted in time release micro encapsulation, improved stability, and increased aqueous solubility of various drugs.
Cyclodextrins are known generally to improve the dissolution rate of drugs. The complexes formed are, however, also stable in aqueous solution, so that the improvement in dissolution is accompanied by an increase in the saturation solubility of the drug. Unfortunately the very .beta.-cyclodextrin that forms the most stable complexes with most drugs has the lowest water solubility, so that drugs that are complexed with it cannot be brought into solution at therapeutic concentrations. The reason for this appears to be due to the crystalline structure of .beta.-cyclodextrin itself.
Chemical modification of cyclodextrins is known to modulate their properties. Electroneutral cyclodextrins have been described by Parmerter et al (U.S. Pat. No. 3,453,259), and Gramera et al (U.S. Pat. No. 3,459,731). These are obtained by the condensation reaction of cyclodextrins with various epoxides or organic halides.
Other derivatives include cyclodextrins with cationic properties (Parmerter (I); U.S. Pat. No. 3,453,257), insoluble crosslinked cyclodextrins (Solms; U.S. Pat. No. 3,420,788), and cyclodextrins with anionic properties (Parmerter (II); U.S. Pat. No. 3,426,011). Among the cyclodextrin derivatives with anionic properties, carboxylic acids, phosphorus acids, phosphinous acids, phosphonic acids, phosphoric acids, thiophosphonic acids, thiophosphinic acids, and sulfonic acids (see Parmerter (II), supra), have been appended to the parent cyclodextrin.
Cyclodextrins have found applications in pharmaceutical delivery systems. As a "host" for "guest" drug molecules, these inclusion (clathrate) complexes have shown increased aqueous solubility for pharmaceuticals with intrinsically low aqueous solubility (Jones; U.S. Pat. No. 4,555,504).
This solubilization results in the improved bioavailability for some drugs. As a clathrate complex some drugs have shown improved chemical stability in aqueous solution (Harada et al; U.S. Pat. No. 4,497,803 and Hayashi et al; U.S. Pat. No. 3,816,394). In addition, cyclodextrins have proved effective in controlling the release of highly water soluble pharmaceuticals (Friedman; U.S. Pat. No. 4,774,329).
Despite this pharmaceutical utility, cyclodextrins are not without their limitations. The use of cyclodextrins in the clinical setting is limited to oral and topical dosage forms as the cyclodextrins exhibit nephrotoxicity upon entering the body unmetabolized. Since mammalian enzymes are specific for the degradation of linear starch molecules, the cyclodextrins remain largely unmetabolized and accumulate, due to their recirculation and readsorption, in the proximal tubule cells.
Cyclodextrins and their derivatives are mostly crystalline solids and concentration in the renal tissue is followed by crystal formation causing necrotic damage to the cells. Despite forming water soluble clathrate complexes, the crystalline cyclodextrin drug complexes have been limited in their utility to sublingual administration.
Efforts have been made to inhibit crystal formation in cyclodextrin drug complexes by derivatizing parent cyclodextrins in a non-specific manner to obtain amorphous mixtures containing many cyclodextrin derivative components (cf. Pitha; U.S. Pat. Nos. 4,596,795 and 4,727,064). These mixtures prevent the crystallization processes seen with single compounds, providing a lowering of toxicity.